Multi-well microplates play an important role in conventional chemical, biological, pharmacological and related processes that are designed to analyze and/or synthesize large numbers of small fluid samples. Such conventional processes normally employ multi-well microplates as tools when processing, shipping and storing the small liquid samples. Many of these processes achieve high-throughputs by applying modern automation techniques, including robotics. In recent years, efforts have been directed at integrating the different prevailing microplate apparatus into the automation equipment of these high-throughput processes. Such integration efforts, however, have had only limited success. Specifically, spillage, leakage, evaporation loss, airborne contamination and inter-well cross contamination of liquid samples are some of the common deficiencies that limit the application of many standard microplate assemblies in high-throughput systems. Consequently, one of the most critical problems confronting designers of microplate apparatus has been finding techniques of preventing the loss and contamination of well contents without unduly complicating the structures and/or handling requirements of a microplate assembly.
A standard microplate assembly normally comprises a microplate having a plurality of open wells and an optional closure device for sealing the wells shut. Commonly available microplates generally embody a unitary molded structure comprising a rigid frame for housing a plurality of open wells arranged in a rectangular array. Standard well closures include resilient, press-fit stoppers, rigid screw caps, adhesive films and the like. Microplates come in a range of sizes; a well may be sized to hold as high as five milliliters or as low as only a few microliters of liquid. In addition, microplates come in a variety of materials, such as polystyrene, polycarbonate, polypropylene, TEFLON, glass, ceramics and quartz. Conventional microplates found in many high-throughput systems comprise a ninety-six well geometry molded into an 8 by 12 rectangular array of open circular wells. Microplates with lower well densities (e.g., 24 and 48 wells) and higher well densities (e.g., 384 and 1536 wells) are also available. Nanoliters is a trend for 1536 well plates.
An important microplate application exists in high-throughput organic synthesis (HTOS) systems. HTOS is an important tool for the accelerated synthesis of small organic molecules. HTOS systems employ a variety of automation techniques, which significantly reduce the time required for the development of commercially acceptable compounds in the pharmaceutical, agrochemical and other specialty chemical industries. Most conventional HTOS systems simultaneously synthesize large groups of compounds while using standard microplate assemblies for the reaction, purification and shipment of such compounds. Another important microplate application exists in high-throughput screening (HTS) systems, which examine biological samples for desired properties. HTS systems usually examine the samples while they are contained in the wells of conventional microplates. As such, automatic apparatus must manipulate conventional microplates and their contents during a typical HTS process. Consequently, a primarily requirement of a microplate assembly for use in HTOS and HTS systems is an ability to securely maintain a controlled environment for a liquid sample while the assembly is being manipulated in an automation process. In addition, a microplate assembly must provide means for adding reagents or other materials to an individual well or to multiple wells simultaneously. Some automation devices take some time to add reagents and this could be problematic for an assay requiring all reactions to take place at the same time. Further, a microplate assembly must allow for the mechanical mixing of well contents without risking spills, leaks or cross contamination.
Many HTOS systems deliver multiple samples as solutions of pre-dissolved compounds in microplate assemblies to various locations throughout the world. To prevent a loss of these solutions of pre-dissolved compounds from occurring during delivery, suppliers often convert the solutions into solids prior to shipment by freezing or other methods. Shipping compounds as solids rather than liquids, however, creates problems in dissolution that can complicate and inhibit subsequent sample evaluation procedures. Further, an unstable solid material may disperse on opening of a closed well prior to re-dissolution. Consequently, those skilled in the art have recognized that HTOS systems should preferably deliver solutions of compounds in their stable liquid form.
Accordingly, it is desirable to provide a method and apparatus that delivers reagents or other materials to each individual well or to multiple wells simultaneously and efficiently. There is a need to be able to add reagents simultaneously for all well assays having a time-based, or kinetic character.